The overall objective of this research is to test the hypothesis that monoclonal antibodies to radiation-induced tumor neoantigens cause therapeutically beneficial immune responses in cancer models. We will study the efficacy of a mouse monoclonal antibody to a radiation-inducible neoantigen and analyze immune effector cell activation to control cancer. This strategy complements the use of existing therapeutic antibodies by inducing additional cell surface tumor antigens for simultaneous targeting by multiple antibodies. Presently, therapeutic antibodies for cancer are limited to antigens that are either specific to cancer or are over-expressed in cancers. Not only is the number of such antigens limited, but they also tend to be over-expressed in a small percentage of patients (e.g. 30% breast cancers express Her2/neu). In contrast, radiation-inducible antigens are expressed in nearly all cancers tested thus far and expand the number of therapeutic targets for antibody development. The principles of radiation-inducible neoantigens are that cancer cells over-express certain intracellular proteins including TIP-1, the focus of this proposal. Cancer cells respond to ionizing radiation by transporting these proteins to the cell surface. In order to investigate the potential of therapeutics targeted to radiation- induced tumor antigens, we developed a monoclonal antibody to the radiation-induced antigen, TIP-1. We propose studies to test the hypothesis that the antibody to this antigen induces therapeutic anti-tumor immune responses. Tax interacting protein-1 (TIP-1) is a membrane-associated protein that is over-expressed in poor prognosis cancer including non-small cell lung cancer. We recently found that TIP-1 undergoes radiation- induced translocation to the cell surface. Cancer specific antibody binding is achieved in vivo for several days by anti-TIP-1 antibody administration after irradiation, and optical imaging and immunohistochemical staining indicated that this antibody (1A6H14) achieves specific binding to irradiated cancer in mouse models. As noted above, the proposed approach is dependent on the induction of anti-tumor immune responses (antibody- dependent cellular cytotoxicity, ADCC; antibody-dependent cellular phagocytosis, ADCP; and perhaps an adaptive T cell response) based on opsonization of tumor cells by the anti-TIP-1 mAb and recognition of the Fc by Fc receptors on natural killer (NK) cells, dendritic cells (DC) and other cell types. Importantly, it has been shown that several approved anti-cancer therapeutic mAb, including trastuzumab, cetuximab and rituximab, have portions of their mechanisms of action through ADCC and ADCP. PUBLIC HEALTH RELEVANCE: Because of the poor prognosis of non-small cell lung cancer even with current therapies, there is a need for new treatments. The proposed studies will investigate a novel approach to cancer treatment: the use of monoclonal antibodies to radiation-induced tumor antigens.